This invention relates to invasive medical devices for delayed/sustained release of pharmaceutical compositions from a polymer that is coated or incorporated into the devices. The purpose of the coating or delivery system on these devices is to reduce, control or even prevent the inflammation and infection that occur with prolonged use of these devices.
A longstanding problem is in the area of medical devices directly contacting the mucosa and the tissue of the body for prolonged periods of time, thereby causing a reaction by the body against those devices, as is the case with tracheotomy tubes, endotracheal tubes, tracheal tubes, stoma stents, laryngeal/bronchial stents, laryngeal keels, esophageal reconstruction tubes, nasal/paranasal tubes or splints, nasogastric tubes, ear ventilation (PE) tubes, gastrostomy tubes, foley catheters, intravenous catheters and all kinds of indwelling percutaneous catheters. This reaction often consists of an inflammation and/or infection that frequently progresses into a pathological process. There is also a longstanding problem with infection associated with this process.
For example, prolonged intubation using endotracheal tubes or tracheotomy tubes may cause subglottic stenosis. Acquired subglottic stenosis consequent to prolonged intubation is a much dreaded and morbid condition. This disease is reported to develop in 4% to 8% of those infants and neonates who require sustained intubation, as described by Marshak G., et al., Pediatr. Clin. North Am. 28: 941-948 (1981). In both adults and children, the incidence is increasing with increasing survivorship in intensive care units. The pathophysiology of acquired subglottic stenosis is well known, for example, as described by Cotton, R. T., et al: In Paparella and Shumrick, editors, Otolaryngology, Vol. II: Chronic laryngeal and tracheal stenosis (W. B. Saunders, Philadelphia, 1980); Hawkins, D. B. Laryngoscope 87:339 (1977); and Biller, H. F. et al, Ann. Otol. Laryngol. 79: 1084-7 (1970).
The endotracheal tube causes pressure necrosis at the point of interface with tissue, leading to mucosal edema and ulceration. As ulceration deepens, there is an interruption of normal ciliary flow with mucociliary stasis leading to secondary infection and perichondritis, as reviewed Sasaki, C. T., et al., Laryngoscope 89:857-865 (1979). With further infection, chondritis and cartilaginous necrosis occur, especially with collapse of the airway during inspiration. Healing occurs by secondary intention in the areas of ulceration and deposition of fibrous tissue in the submucosa, leading to subglottic stenosis.
The management of this problem is both controversial and frustrating, as evidenced by the wide spectrum of therapeutic procedures advocated, and the fact that all of them give far from ideal results. Of the non-invasive treatment modalities available, administration of corticosteroids, alone or with systemically administered antibiotics has been advocated by Borowiecki, B., et al, Ann. Otol. Rhinol. Laryngol, 86:835-40 (1977); and Suspance, J. Ann. Otol. Rhinol. Laryngol. 92: 377-382 (1983). Corticosteroids are known to have an anti-inflammatory effect on the exudative and destructive phases of injury as well as during the period of healing. Since the basic principle in prevention is to control, reduce or even prevent submucosal fibrosis, systemic steroids have been administered to reduce inflammation during the exudative and destructive phase of tissue injury, and in the period of healing or scarring, or both. Furthermore, recently, inhaled aerolized corticosteroids have been shown to be quite beneficial in reducing the subglottic injury in animals, Kryzer, T. C., et al: "Effects of aerolized Dexamethasone on acute subglottic injury", presented at the Fourth Annual Symposium of the Uniformed Services University of Health Services (Bethesda, Md., May 1990). The drawback to systemic steroid treatment is that it results in a generalized immunosuppression and decrease in healing, as well as other undesirable side effects.
Antimicrobial therapy has been advocated to control localized subglottic bacterial infection, which has been suggested as contributing to the progression of the disease. Experimental studies in dogs have shown that the timing and duration of therapy after injury are of great importance in reducing the activity and sequelae of sclerosing chondritis, as reported by Croft, C., et al, Laryngoscope 89:482-489 (1979). With the continuous presence of the endotracheal or tracheotomy tube, granulation tissue may occur, not only perpetuating the local infection but also sometimes blocking the airway and necessitating emergency surgical intervention. Experimental studies in animals have shown that the key in this form of treatment is to achieve a high local concentration of antibiotics and to maintain the treatment throughout the period of intubation, Kryzer, T. C., (1990). This, until now, has not been the standard of clinical care because of the cost and the potential systemic side effects of such prolonged treatment and of technical difficulties, as some patients remain intubated for months.
Every patient who is intubated or undergoes a tracheotomy runs the risk of developing subglottic stenosis. This is especially true for the pediatric population who has a relatively narrow airway and is susceptible to airway compromise even with minor subglottic inflammation. To understand the magnitude of the problem, a review of the records on tracheotomy and prolonged endotracheal intubation was completed from the Vital & Health Statistics data collection. In 1973, 42,000 tracheotomies were performed in the United States alone; extrapolating to 1990, 65,000 were done in the USA. Of these, especially in children, a large number will develop mucosal inflammation and stomal granulation tissue if the tube is left long enough (in children almost all will get this problem and one half of them need some kind of surgical intervention for the granulation tissue). A much larger number of patients are expected to undergo prolonged intubation, especially with the introduction of improved intensive care units. The exact number of these patients is not available; although about 4,000,000 surgical procedures necessitating intubation were done in 1973 in the United States alone.
Another long standing problem of significance is chronic nasal and paranasal disease, with a prevalence of about 40 million people in the United States alone. Endoscopic sinus surgery is being increasingly done in these patients with the availability of new telescopic instruments and comprehensive training in the field. The most common complication of this operation is scarring and stenosis. There are no truly effective means to prevent or treat this problem.
Still another problem involving treatment of the nasopharyngeal region of the body is the treatment of caustic burns to the esophagus. The most common cause of esophageal stricture in children is the accidental ingestion of strong corrosive agents, as reported by Haller, J. A., et al, J. Ped. Surg. 6(5): 578-584 (1971). In adults and teenagers, caustic injuries occur as a result of an attempt at suicide. By far the most common agent ingested is concentrated sodium hydroxide in the form of commercial toilet bowl and oven cleaners. The result of the ingestion is severe inflammation combined with ulceration, vascular thrombosis and liquefaction necrosis, which may lead to varying degrees of stricture formation.
In the past, treatment was based on repeated and continuing esophageal dilation to prevent ultimate severe strictures, although this has been abandoned. In its place, an indirect treatment was introduced, which consists of systemic administration of corticosteroids to decrease the inflammatory reaction, and antibiotics to help prevent secondary infection. Animal studies have shown that after the acute inflammatory reaction, fibroblasts proliferate over the next two to three weeks, and healing is complete by the end of that time, as reported by Haller, J. A., Pediatrics 34(2): 236-245 (1964). Based on these studies, the prophylactic use of systemic steroids and antibiotics is for the first week to 10 days, with a continuation of systemic steroids for protection against inflammation and fibroblast proliferation for the full three weeks, as described by Haller, et al., (1964); Haller, J. A,, "Caustic burns of the esophagus". Current Therapy in Cardiothoracic Surgery, pp.75-76 (B. C. Becker Inc., 1989).
Another approach to the management of this injury has included the use of an intraluminal esophageal stent to prevent stricture formation. As described by Tucker, J. A. Otol. Clinics North Amer. vol.12, 343-349 (1979), the stent used for adults was a 47 cm silicone tube with a 5/8 inch outside diameter which was kept in place for about 3 weeks. As with the other procedures, the treatment and results are still less than adequate.
Other problems in this area include ear ventilation (PE) tubes. Millions of PE tubes are inserted every year in the United States alone. Of all PE tubes, 20% result in chronic otorrhea and require systemic antibiotics. Those who fail to respond to the systemic antibiotics, sometimes respond to local installation of antibiotics and corticosteroids introduced into the middle ear through the tube. A certain number will need removal of the tube, as reported by Bluestone and Stool, Pediatric Otolaryngology, pp. 321-486, 2nd edition (Saunders Publishing Co, Philadelphia 1990).
The sustained release of biologically active agents from polymers has been shown to be effective in several systems, including implants, ocular inserts, coated intrauterine devices and other similar devices, as described in U.S. Pat. Nos. 3,416,530 to Ness; 3,55,556 to Kliment, et al.; 4,548,990 to Mueller, et al. and 4,888,413 to Domb. In the preferred embodiments, these have utilized bioerodible polymers as the matrix for the drug to be released, usually as a function of diffusion and erosion of the polymer. The advantage of these drug delivery systems is that they provide a sustained/continuous release of drugs locally and at a relatively high concentration in areas of the body, without systemic side-affects, throughout the duration of their release.
Efforts to incorporate antibiotic releasing coatings into catheters have been made. U.S. Pat. No. 4,950,256 to Luthoer and Shanbrom discloses an intravascular catheter having a polymeric coating incorporating an antibiotic. The antibiotic prevents bacterial growth on the catheter when inserted into a blood vessel of the patient. U.S. Pat. No. 3,598,127 to Wepsic discloses a urinary tract catheter formed of a nonpermeable rubber coated with an antibiotic surrounded by an outer coating of a permeable rubber coating through which the antibiotic can diffuse. However, no one has addressed the more difficult problem of inflammation and growth of tissue around a catheter.
It is therefore an object of the present invention to provide medical devices which are anti-microbial and anti-inflammatory.
It is a further object of the present invention to provide medical devices having prolonged low-dose, localized release of anti-microbial and anti-inflammatory agents.
It is a still further object to provide medical devices for insertion or implantation into tissue that are resistant to infection and inhibit inflammation and growth of tissue around and onto the device.